U‐shaped dose‐dependent effects of BmK AS, a unique scorpion polypeptide toxin, on voltage‐gated sodium channels

Abstract

Background and purpose: Buthus martensi Karsch (BmK) AS is a scorpion polypeptide toxin, said to target the voltage-gated sodium channels (VGSCs). However, the mechanism of action of BmK AS on the VGSCs has yet to be defined. Experimental approach: We examined the electrophysiological effects of BmK AS in a wide dose range on the rat brain-type VGSC a-subunit, rNav1.2a, heterologously expressed in Xenopus oocytes and on the VGSCs endogenously expressed in the dorsal root ganglion neuroblastoma ND7-23 cell line. Key results: In the oocytes, BmK AS depolarized the voltage dependence of activation and inactivation of rNav1.2a at 0.1 and 500 nM whereas these parameters were hyperpolarized at 1 nM. In ND7-23 cells, BmK AS hyperpolarized the voltage dependence of activation and inactivation at 0.1, 1 and 100 nM but not 10 nM. BmK AS also hyperpolarized the voltage dependence of recovery from inactivation at 0.1 and 100 nM and slowed the recovery kinetics at all concentrations, but the effects of 1 and 10 nM were relatively smaller than those at 0.1 and 100 nM. Moreover, the inactivation of VGSCs was potentiated by 10 nM BmK AS in both systems, whereas it was inhibited by 0.1 or 100 nM BmK AS in the oocytes or ND7-23 cells respectively. Conclusions and implications: BmK AS modulated the VGSCs in a unique U-shaped dose-dependent manner, which could be due to the opposing effects of binding to two distinct receptor sites on the VGSCs.

Scorpion Venom Research Around The World: Chinese Scorpion Mesobuthus martensii Karsch

“…In the Xenopus oocytes, BmK AS depolarized the voltage dependence of activation and inactivation of Na v 1.2 at 0.1 and 500 nM whereas hyperpolarized them at 1 nM. In the ND7-23 cells, BmK AS hyperpolarized the voltage dependence of activation and inactivation at 0.1, 1 and 100 nM but not 10 nM (Zhu et al 2009). This unique U-shaped dose-dependent modulation pattern of BmK AS could also be observed for Na v 1.3 (Liu et al 2012).…”

PKA phosphorylation reshapes the pharmacological kinetics of BmK AS, a unique site-4 sodium channel-specific modulator

“…Based on the previous pharmacological studies of BmK AS on sodium channels, it was concluded that the voltage-dependent activation and inactivation of these VGSC subtypes displayed a U-shaped shift in response to different concentration of BmK AS (0.1, 1, 10, 50, 100, 500 nM)1416. In the current research, three of the concentrations of BmK AS (1, 10 and 100 nM) were chosen to investigate the pharmacological characteristics of BmK AS on Na v 1.2α with or without β1 subunit.…”

“…BmK AS was found to stimulate noradrenaline release from rat hippocampus slices by augmentation of sodium influx13. Electrophysiological studies also demonstrated that BmK AS could depolarized the voltage-dependence of fast or slow inactivation, resulting in slower inactivation14.…”

“…at high concentrations, BmK AS increased the cell excitability, while at low concentrations, BmK AS suppressed the cell excitability14. The U-shaped relationship of VGSC modulation may be also dependent on VGSCs subtypes or tissue/cell environment.…”

Activation of mammalian target of rapamycin contributes to pain nociception induced in rats by BmK I, a sodium channel-specific modulator

“…BmK neurotoxins targeting membrane channels such as voltage-gated Na + channels (VGSCs) and K + channels are the prime suspects [19][20][21][22][23][24][25] . BmK I, a toxin specific to VGSC receptor site 3, increases Na + currents and delays the inactivation of VGSCs [26] .…”